BACKGROUND: Severe TBI is associated with a high rate of mortality and long-term morbidity. Comatose patients with TBI routinely undergo endo-tracheal intubation to protect the airway, prevent hypoxia, and control ventilation. In many places, paramedics perform intubation prior to hospital arrival. However, it is unknown whether this approach improves outcomes.

METHODS: In a prospective, randomized, controlled trial, we assigned adults with severe TBI in an urban setting to either prehospital rapid sequence intubation by paramedics or transport to a hospital emergency department for intubation by physicians. The primary outcome measure was the median extended Glasgow Outcome Scale (GOSe) score at 6 months. Secondary end-points were favorable versus unfavorable outcome at 6 months, length of intensive care and hospital stay, and survival to hospital discharge.

RESULTS: A total of 312 patients with severe TBI were randomly assigned to paramedic rapid sequence intubation or hospital intubation. The success rate for paramedic intubation was 97%. At 6 months, the median GOSe score was 5 (interquartile range, 1-6) in patients intubated by paramedics compared with 3 (interquartile range, 1-6) in the patients intubated at hospital (P = 0.28).The proportion of patients with favorable outcome (GOSe, 5-8) was 80 of 157 patients (51%) in the paramedic intubation group compared with 56 of 142 patients (39%) in the hospital intubation group (risk ratio, 1.28; 95% confidence interval, 1.00-1.64; P = 0.046). There were no differences in intensive care or hospital length of stay, or in survival to hospital discharge.

CONCLUSIONS: In adults with severe TBI, prehospital rapid sequence intubation by paramedics increases the rate of favorable neurologic outcome at 6 months compared with intubation in the hospital.

Notes & Commentary:

This well designed, conducted and reported randomised controlled trial (RCT) of prehospital rapid sequence induction (RSI) of anaesthesia & intubation in traumatic brain injury is the first RCT of prehospital RSI of any reasonable quality in trauma. (See the 2009 Cochrane Review "Emergency intubation for acutely ill and injured patients"). Furthermore the researchers moved beyond mortality as the primary outcome to a more comprehensive assessment of outcome (dependency). They found no difference in hospital outcomes but a strong signal for "good neurological outcome" (normal to moderate disability) in the Prehospital RSI group.

Overall the study was well conducted. Subjects were block randomised by paramedic crew via sealed opaque envelopes. The study was conducted over nearly four years. There were a lot of exclusions - 1045 patients were screened but only 312 enrolled. Most exclusions were either because the patient was being transported by air, was less than 10 minutes from hospital or RSI skills were not available at scene.

As with all such studies there are many questions to answer. Despite the observed outcome differences, there was little difference in the 2 groups on hospital arrival, and in particular there was no difference in their PaO2, O2 saturations or PaCO2 measurements. What then was the benefit of prehospital RSI - does it avoid fluctuations in these variables or is it reducing spikes in intracranial pressure? The preshopital RSI patients statistically spent 12 minutes longer on scene, received approximately 500mls more crystalloid prehospitally, and were colder (by 0.6 degrees C). Is the observed effect due to the protective effects of this mild relative hypothermia (mean 35.0 degrees C).

Additionally there was overall benefit but it was not clear which subgroup had the most benefit from prehospital RSI. There was a trend to suggest that those age <60 received the most benefit. However the trial was really too small for these subgroup analyses and none of the reported subgroups showed worse outcomes with the study intervention. This study joins the list of recent studies showing that good quality clinical trials can be conducted in trauma care, even in the prehospital environment. There is really no longer any excuse for poor design, conduct or reporting of trauma trials. While a further large trial is warranted, this is strong support for prehospital RSI.

Abstract:

BACKGROUND: Hypertonic fluids have potential benefit in the resuscitation of severely injured patients because of rapid restoration of tissue perfusion, with a smaller volume, and modulation of the inflammatory response, to reduce subsequent organ injury.

RESULTS: A total of 853 treated patients were enrolled, among whom 62% were with blunt trauma, 38% with penetrating. There was no difference in 28-day survival-HSD: 74.5% (0.1; 95% confidence interval [CI], -7.5 to 7.8); HS: 73.0% (-1.4; 95% CI, -8.7-6.0); and NS: 74.4%, P = 0.91. There was a higher mortality for the postrandomization subgroup of patients who did not receive blood transfusions in the first 24 hours, who received hypertonic fluids compared to NS [28-day mortality-HSD: 10% (5.2; 95% CI, 0.4-10.1); HS: 12.2% (7.4; 95% CI, 2.5-12.2); and NS: 4.8%, P < 0.01].

CONCLUSION: Among injured patients with hypovolemic shock, initial resuscitation fluid treatment with either HS or HSD compared with NS, did not result in superior 28-day survival. However, interpretation of these findings is limited by the early stopping of the trial. Clinical Trial Registration: ClinicalTrials.gov, NCT00316017].

Notes & Commentary:

This randomised controlled trial should be the final nail in the coffin for hypertonic saline in the resuscitation of haemorrhagic shock. The study was conducted by the Resuscitation Outcomes Consortium - a multicentre clinical trial network of trauma centres and their affiliated emergency medical services. The study was designed to enrol 3726 patients, but was stopped for futility and the possibility of harm in terms of increased mortality in the hypertonic saline sybgroups.

Overall there was no difference in 28-day mortality or any of the reported outcomes. Mortality was 25.6% for the NS group versus 27% for HS and 25.5% for HSD:

The reason for early stopping of the trial is rather tenous. Stopping a trial for "futility" lays a trial open to the vagaries of randomness and assumes that what happened in the enrolled patients was fully representative of the final study cohort. The trial was also stopped because of concern s about possibly increased mortality in a group of patients who did not receive blood transfusions. This was an observation made on a sub-group of patients that had not been identifed a priori and had not reached statistical significance. This is also a post-randomisation variable that has clear potential for interaction with the study intervention. Much of the paper is given over to the post-hoc analysis of this subgroup and presents lots of conjecture but few real conclusions.

The authors also state that the 'The DSMB [data and safety monitoring board] also noted that the setting of an exception to informed consent study warranted an abundance of caution'. Personally I think this a lousy statement that does a disservice to those subjects who did participate in the trial and is contrary to the fundamental ethics of clinical trials. Emergency consent procedures have been developed around the world to allow the study of acute diseases. Clinical trials should be designed and conducted optimally within these structures. It is not appropriate to skew robust clinical trial methodolgy and the interpretation of clinical trial data because of the ethical setting - in fact it is borderline unethical to do so (IMHO).

Anyway - fundamentally the trial is negative and it is unlikely that a large treatment effect was missed due to the early termination. There is no clinical advantage to the resuscitation of haemorrhagic shock with hypertonic saline. Whether this has any bearing on the role of HS versus mannitol in the setting of traumatic brain injury with or without hypovolaemia is unclear.